1 Appendix 1. Literature Search Strategy 2 Among the Medical Subject Headings (MeSH) searched were estrogens, conjugated; conjugated 3 equine estrogen; Premarin; estradiol; Vagifem; Estring; Estrace; estriol; estrogen replacement 4 therapy; atrophy; vaginal diseases; atrophic vaginitis; vaginal discharge; dysuria; urinary 5 incontinence; overactive bladder; sexual dysfunction; dyspareunia; randomized controlled trial; 6 controlled clinical trial; comparative study; prospective study; cross-over study; meta-analysis; 7 and systematic review. We did not attempt to identify unpublished articles or abstracts, and we 8 did not contact study authors. The search was limited to human subjects and English language. 9 Reference lists of selected articles and review papers were screened for additional eligible 10 references. 11 12 Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, et al. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. Obstet Gynecol 2014;124. The authors provided this information as a supplement to their article. © Copyright 2014 American College of Obstetricians and Gynecologists. Page 1 of 4 13 Appendix 2. Non–Placebo-Controlled Studies of Vaginal Estrogen in Women With 14 Genitourinary Syndrome of Menopause Study Author, Country, y Study Quality Intervention (n) Comparator (n) Conjugated estrogen cream⁺ 1 g Daily 21 d, then none 7 d (63) Conjugated estrogen cream 2 g 3x per wk (67) Conjugated estrogen cream 2 g 3x per wk (67) Estriol 0.5 mg cream Daily 2 wk, then 3x per wk (82) Estriol 1 mg ovule Daily 2 wk, then 2 ovules 1x per wk (103) OCP vaginally 1x per wk (20) Ayton,(31) Australia, 1996 A Estradiol vaginal ring, once (131) Bachmann,(32) USA, 1997 Nachtigall,(33) USA, 1995* Barentsen,(34) The Netherlands, 1997 Capobianco,(35) Italy, 2012 B Estradiol vaginal ring, once (129) Estradiol vaginal ring, once (129) Estradiol vaginal ring, once (83) * A A Chompootaweep,(36) Thailand, 1998 B Dickerson,(37) USA, 1979 Dugal,(38) Norway, 2000 Henriksson,(39) Sweden, 1994 Kicovic,(40) Italy, 1980 B A A C Estriol 1 mg ovule Daily 2 wk, then 2 ovules 1x per wk plus PFMT (103) Conjugated estrogen cream 1 g 3x per wk for 1 wk, then 2x per wk for 1 wk, then 1x per wk for 6 wk (20) Estradiol 0.01% cream 0.2 mg Daily 2 wk (20) Estradiol vaginal tablet 25 μg Daily 2 wk, then 2x per wk (46) Estradiol vaginal ring, once (112) Estriol cream 1 mg Daily 3 wk, then 2x per wk (23) Lose,(41) Denmark, 2000 B Estradiol vaginal ring Every 12 wk (134) Manonai,(42) Thailand, 2001 Mattson,(43) Sweden, 1983 Mattson,(44) Sweden, 1989 Mettler,(45) Germany, 1991 B Estradiol vaginal tablet 25 μg Daily 2 wk, then 2x per wk (27) Estriol cream 0.5 mg Daily 2 wk, then 2x per wk (15) Estradiol vaginal tablet 25 μg Daily 3 wk, then 2x per wk (20) Estradiol vaginal tablet 25 μg Daily 2 wk, then 1x per wk (17) B C C Conjugated estrogen cream 2 g Daily 2 wk (10) Estriol vagitory 0.5 mg Daily 2 wk, then 2x per wk (46) Estriol pessary 0.5 mg Daily 3 wk, then 2x per wk (53) Estriol cream 0.5 mg (30) or Estriol suppository 0.5 mg (21) Daily 3 wk, then 2x per wk Estriol pessary 0.5 mg Daily 3 wk, then every other day (117) Conjugated estrogen cream 1 g Daily 2 wk, then 2x per wk (63) Estriol suppository 0.5 mg Daily 2 wk, then 2x per wk (15) Estradiol vaginal tablet 50 μg Daily 3 wk, then 2x per wk (20) Estradiol vaginal tablet 25 μg Daily 2 wk, then 2x per wk (34) FollowUp Duration 12 wk 12 wk 12 wk 12 wk 24 wk 8 wk 2 wk 24 wk 12 wk 16 wk 24 wk 12 wk 8 wk 9 wk 52 wk Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, et al. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. Obstet Gynecol 2014;124. The authors provided this information as a supplement to their article. © Copyright 2014 American College of Obstetricians and Gynecologists. Page 2 of 4 Rioux,(46) Canada, 2000 Trevoux,(47) France, 1982 Weisberg,(48) Australia, 2005 Antoniou,(49) Greece, 1997 Botsis,(50) Greece, 1997 Gupta,(51) USA, 2008 Holmgren,(52) Sweden, 1989 Long,(53, 54) China, 2006 Biglia,(55) Italy, 2010 A Estradiol vaginal tablet 25 μg Daily 2 wk, then 2x per wk (80) Estriol cream 0.5 mg Daily 3 wk, then 2x per wk (54) Estradiol vaginal ring Every 12 wk (126) Estradiol vaginal ring every 12 wk and 100mg vaginal progesterone suppository 7 d per mo (28) Conjugated estrogen cream 1 g Frequency unspecified (36) Estradiol vaginal ring, once (12) C Estradiol vaginal ring, once (11) B Conjugated estrogen oral tablet 0.625mg per day (27) Estriol cream 0.25mg 2x per wk (10) or estradiol vaginal tablet 12.5 μg 2x per wk (8) Estradiol vaginal tablet 25 μg Daily 2 wk, then 2x per wk (21) Conjugated estrogen cream 2 g Daily (15) B C A B B C Ekin,(56) Turkey, 2011 Nachtigall,(57) USA, 1994 C Parsons,(58) USA, 2003 and Kessel,(59) USA, 2003† Raghunandan,(60) India, 2010# Pinkerton,(61) USA, 2003 B Conjugated estrogen cream 1 g Daily 2 wk, then 2x per wk (46) B Conjugated estrogen cream 1 g Daily 2 wk, then 2x per wk (25) Estradiol vaginal ring every 12 wk and daily oral placebo (45) Raz,(62) Israel, 2003 C A A Estriol pessary 0.5 mg 2x per wk and daily oral placebo (86) Conjugated estrogen cream 2 g Daily 21 d, then none 7 d (79) Estriol suppository 0.5 mg Daily 3 wk, then 2x per wk (28) Estradiol vaginal tablet 25 μg Daily 2 wk, then 2x per wk (59) Transdermal estradiol 50 μg per d and levonorgestrel-releasing intrauterine device (28) 24 wk Tibolone 2.5 mg orally Daily (36) Transdermal estradiol 14 μg per d (12) Vaginal estradiol ring 20-30 μg per d (11) Conjugated estrogen cream 1 g Daily (30) Non-hormonal moisturizer (Replens®) 2.5 g 2x per wk (8) Hyaluronic acid 5 mg tablet Daily (21) Non-hormonal moisturizer (Replens®) 3x per wk (15) Non-hormonal moisturizer (Replens®) Daily 2 wk, then 2x per wk (47) Nonhormonal KY lubricant gel Daily 2 wk, then 2x per wk (25) Estradiol vaginal ring every 12 wk and daily oral raloxifene 60 mg (46) Vaginal pessary placebo 2x per wk and daily oral nitrofurantoin macrocrystal 100 mg (85) 6 mo 8 wk 48 wk 52 wk 12 wk 12 wk 12 wk 12 wk 8 wk 12 wk 12 wk 12 wk 6 mo 9 mo 15 wk, week; PFMT, Pelvic Floor Muscle Therapy; OCP, oral contraceptive pill containing 250 μg 16 levonorgestrel plus 30 μg ethinyl estradiol. Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, et al. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. Obstet Gynecol 2014;124. The authors provided this information as a supplement to their article. © Copyright 2014 American College of Obstetricians and Gynecologists. Page 3 of 4 17 ⁺ Conjugated estrogen cream (Premarin) concentration in all studies involved: 0.625 mg per 1 g 18 cream. 19 *, Supplemental companion paper to Bachmann 1997.(32) 20 † 21 receiving conjugated estrogen or non-hormonal moisturizer creams were considered for this 22 review. 23 # 24 0.5 gm 2% testosterone (1 mg) cream; only the conjugated estrogen cream versus non-hormonal 25 lubricant gel comparison was considered for this review. , Study also contains randomization to oral Raloxifene or placebo; only the oral placebo patients , Study also contains a third comparison group receiving both conjugated estrogen cream and Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, et al. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. Obstet Gynecol 2014;124. The authors provided this information as a supplement to their article. © Copyright 2014 American College of Obstetricians and Gynecologists. Page 4 of 4